Trametinib showed a meaningful benefit for treating BRAF-mutated melanoma in a phase III trial.

About 50% of melanomas harbor activating mutations in BRAF. The protein kinase BRAF activates the MEK kinase, which, some evidence suggests, has a central role in both BRAF- and NRAS-mutated melanomas and may be an effective therapeutic target in many tumors, even those without BRAF V600E mutations. In phase I and II trials, trametinib, a small-molecule inhibitor of MEK1 and MEK2, caused tumors to regress and disease to stabilize in V600E or V600K BRAF-mutated melanomas.


In this phase III study funded by the manufacturer of trametinib, 322 metastatic melanoma patients with V600E or V600K BRAF mutations received either oral trametinib or dacarbazine or paclitaxel chemotherapy. (Chemotherapy recipients whose disease progressed were able to cross over to trametinib.) Median progression-free survival was 4.8 months in trametinib recipients and 1.5 months in chemotherapy recipients — a significant difference (hazard ratio for progression with trametinib, 0.45; 95% confidence interval, 0.33 to 0.63). At 6 months, the rate of overall survival was significantly higher with trametinib than with chemotherapy (81% vs. 67%) despite crossover (HR for death with trametinib, 0.54; 95% CI, 0.32 to 0.92). Disease stabilized in 56% of trametinib recipients (20% had partial response; 2% had complete response). Common adverse effects included rash, diarrhea, and peripheral edema; no secondary skin proliferations were observed. Like vemurafenib recipients, most patients relapsed after treatment ended.


Citation(s):

Flaherty KT. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012 Jun 4; [e-pub ahead of print].